title: CO2/HCO3(-)- and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor.
abstract: The second messenger molecule cAMP is integral for many physiological processes. In mammalian cells, cAMP can be generated from hormone- and G protein-regulated transmembrane adenylyl cyclases or via the widely expressed and structurally and biochemically distinct enzyme soluble adenylyl cyclase (sAC). sAC activity is uniquely stimulated by bicarbonate ions, and in cells, sAC functions as a physiological carbon dioxide, bicarbonate, and pH sensor. sAC activity is also stimulated by calcium, and its affinity for its substrate ATP suggests that it may be sensitive to physiologically relevant fluctuations in intracellular ATP. We demonstrate here that sAC can function as a cellular ATP sensor. In cells, sAC-generated cAMP reflects alterations in intracellular ATP that do not affect transmembrane AC-generated cAMP. In β cells of the pancreas, glucose metabolism generates ATP, which corresponds to an increase in cAMP, and we show here that sAC is responsible for an ATP-dependent cAMP increase. Glucose metabolism also elicits insulin secretion, and we further show that sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo.
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Zippin
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Chen
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Straub
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Hess
authors.forename: Ana
authors.initials: A
authors.lastname: Diaz
authors.forename: Dana
authors.initials: D
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Tso
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
authors.forename: Geoffrey W G
authors.initials: GW
authors.lastname: Sharp
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism*; D002254:Carbonates / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D002254:Carbonates; D007328:Insulin; D002245:Carbon Dioxide; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases; D005947:Glucose; D002118:Calcium
keywords: Adenylate Cyclase (Adenylyl Cyclase); Cyclic AMP (cAMP); Glucose Metabolism; Metabolic Regulation; Pancreatic Islets